Abstract
Histones released into circulation as neutrophil extracellular traps are causally
implicated in the pathogenesis of arterial, venous, and microvascular thrombosis by
promoting coagulation and enhancing clot stability. Histones induce structural changes
in fibrin rendering it stronger and resistant to fibrinolysis. The current study extends
these observations by defining the antifibrinolytic mechanisms of histones in purified,
plasma, and whole blood systems. Although histones stimulated plasminogen activation
in solution, they inhibited plasmin as competitive substrates. Protection of fibrin
from plasmin digestion is enhanced by covalent incorporation of histones into fibrin,
catalyzed by activated transglutaminase, coagulation factor FXIII (FXIIIa). All histone
subtypes (H1, H2A, H2B, H3, and H4) were crosslinked to fibrin. A distinct, noncovalent
mechanism explains histone-accelerated lateral aggregation of fibrin protofibrils,
resulting in thicker fibers with higher mass-to-length ratios and in turn hampered
fibrinolysis. However, histones were less effective at delaying fibrinolysis in the
absence of FXIIIa activity. Therapeutic doses of low-molecular-weight heparin (LMWH)
prevented covalent but not noncovalent histone–fibrin interactions and neutralized
the effects of histones on fibrinolysis. This suggests an additional antithrombotic
mechanism for LMWH beyond anticoagulation. In conclusion, for the first time we report
that histones are crosslinked to fibrin by FXIIIa and promote fibrinolytic resistance
which can be overcome by FXIIIa inhibitors and histone-binding heparinoids. These
findings provide a rationale for targeting the FXIII–histone–fibrin axis to destabilize
fibrin and prevent potentially thrombotic fibrin networks.
Keywords
fibrin(ogen) - fibrinolysis - histones - neutrophil extracellular traps - FXIII
